Neurological disorders that affect the central nervous system, the peripheral nervous system, and the autonomic nervous system strick millions of people worldwide. These varied disorders include, but are not limited to, thalamocortical dysrhythma, neurogenic pain, obsessive-compulsive disorder, depression, panic disorder, Parkinson's disease, schizophrenia, rigidity, dystonia, tinnitus, tremor, and epilepsy. In particular, these and other neurological disorders occur when the coordinate, controlled electrical activity at the cortical level of the brain becomes disrupted, thereby leading to uncoordinated electrical activity and abnormal neuronal oscillation.
In particular, thalamocortical dysrhythmia refers to a neurological and/or psychiatric condition arising from the abnormal rhythmicity in particular components of the thalamocortical circuit Winds et al. (1999) Proc. Natl. Acad. Sci. USA, 96:15222-15227). At the cellular level, the abnormal activity of the thalamic neurons is caused by an increase of low frequency oscillatory activity due to protracted activation of the T type calcium channels because of direct modification of the channel properties or more commonly, abnormal hyperpolarization of the thalamic neurons due to excess inhibition or deafferentation. Such abnormal activity is transmitted to the related cortical area to which the given thalamic neurons are oscillating generating a recurrent attractor that is maintained by the recursive nature of the circuit. At the macrocellular level, the abnormal rhythmicity interferes with the communication among and between different regions of the brain, and thereby impairs the motor and cognitive skills that are controlled by those regions of the cortex.
Spike output in neuronal cell types is affected by low-voltage-activated Cav3-type calcium currents arising from the Cav channels. Low-voltage-activated (LVA) calcium currents provide an important contribution to spike output patterns of neurons. Cav3-type channels are recognized as key determinants of LVA calcium-dependent responses, including low-threshold calcium spikes (LTS), bistable behavior, rebound depolarizations and augmentation of synaptic responses. Cav3-type channels are important to cell and circuit functions that range from sensory and pain transmission through thalamocortical sleep-wake cycles. The three isoforms of the Cav3-type calcium channel, i.e., Cav3.1, Cav3.2, and Cav3.3, can differ in their voltage-dependent and kinetic properties, demonstrating the potential to differentially affect spike output. In thalamus, differences in the distribution and kinetic properties of Cav3-type currents have been shown to be capable of influencing the nature of oscillatory output of principal cells and inhibitory interneurons involved in the sleep-wake cycle, suggesting a selective distribution or modulation of Cav3 channel isoforms over discrete regions of the cell axis.
There are many drugs currently available for treating neurological disorders. These include, but are not limited to, anticonvulsants, antiepileptics, barbiturates, barbituric acid derivatives, anesthetic agents, tinnitus-treating agents, selective serotonin reuptake inhibitors, antidepressant agents, neuroleptic agents, antihypertensive agents, antipsychotic agents, calcium channel blockers, ACE inhibitors, and beta-blockers. However, many of such drugs are limited in their effectiveness and by their significant side effects. For example, some of these drugs are known to cause lightheadedness, depression insomnia, weakness, fatigue, hallucinations, side-effects which severely limit their use in human population. In particular, beta blockers, anticonvulsants, and benzodiazepines have been shown to be partially beneficial to some patients. However, beta blockers can cause changes in blood pressure and heart rate, and are contraindicated in patients with heart block, asthma, and congestive heart failure.
In addition, some anticonvulsants can cause acute nausea and vomiting, fatigue, sleepiness, confusion and incoordination, while others can cause memory and speech abnormalities, sedation, incoordination, and metabolic dysfunction.
Physical trauma has been used to treat some neurological disorders. For example, certain surgical procedures have been used in the most severe cases of essential tremor, destroying a part of the brain including, the globus pallidus pars interna (GPi) nucleus in the basal ganglia or implanting electrodes into the same area of the brain including connecting them to a pacemaker-like battery that stimulates regions of the brain to diminish the tremor. Such procedures carry a high risk of infection and bleeding or equipment malfunction. Additionally, many existing treatments for some neurological disorders are poorly effective in that they do not stop the disorders completely, and in most instances, they do not prevent or even delay the progression of the disease.
Thus, there is a need for more effective treatments of neurological disorders that have reduced or no side-effects.